6.1. Autoreceptor Regulation of Somatodendritic Dopamine Release
Inhibition of DA release from striatal axon terminals via presynaptic D2-like autoreceptors plays a powerful role in the regulation of striatal [DA]0 (Limberger et al., 1991; Trout and Kruk, 1992; Cragg and Greenfield, 1997; Benoit-Marand et al., 2001). D2-receptors are also expressed and located directly on DA dendrites in VTA and SN (Bouthenet et al, 1987; Hurd et al, 1994; Sesack et al, 1994; Yung et al, 1995). In turn, D2-receptor control of somatodendritic DA release has been documented in SNc indicating that D2 receptors operate as an autoinhibitory mechanism to regulate somatodendritic release (Cragg and Greenfield, 1997). Nonetheless, the degree of control of somatodendritic [DA]0 by this mechanism is less avid than in striatum. Less effective autoinhibition of release, in conjunction with less avid DA re-uptake via the DAT (Nissbrandt et al, 1991; Cragg et al, 1997b), could result in altogether different regulation of [DA]0 in somatodendritic and axon terminal regions.
The modulation of [DA]0 by D2 receptors is less marked in VTA than in SNc, consistent with the higher expression and protein levels of the D2 receptor in ventral tier DA neurons (Hurd et al, 1994). As for differential DAT expression discussed above, regional variation in the management of somatodendritic DA transmission in VTA and SNc by autoreceptor regulation might also contribute to differential susceptibility of these cell groups to degeneration in Parkinson's disease.
6.2. Heteroreceptor Regulation of Somatodendritic Dopamine Release
DA neurons receive significant synaptic input from numerous non-dopaminergic neuron types and concomitantly express somatodendritic receptors for corresponding major classes of neurotransmitters, including GABA, glutamate, 5-HT, and acetylcholine (ACh), as well as co-transmitters like dynorphin and ATP. The role of each of these inputs in the direct heteroreceptor regulation of DA release within the SN and VTA is increasingly being revealed.
Strong inhibitory control of somatodendritic DA release by GABA has been identified, especially in the SNc where both GABAa and GABAb receptors control release (Chen and Rice, 2002). The role of GABA in the VTA is less clear. Although measurements in vivo using microdialysis show that GABAB receptors tonically inhibit DA release in VTA (Giorgetti et al, 2002), in vivo data can be complicated by concomitant activation of long-loop circuits; more direct in vitro methods suggest that GABAa and GABAb receptor control of release in VTA is limited and may depend on the strength and timing of other synaptic input (Chen and Rice, 2002).
Glutamate receptor regulation of somatodendritic DA release can take the form of direct excitation by ionotropic receptors (Araneda and Bustos, 1989; Westerink et al, 1992; Gauchy et al, 1994; Rosales et al, 1994; Chen and Rice, 2002), particularly in the VTA (Chen and Rice, 2002), or heterosynaptic inhibition via AMPA-receptor activation on GABA afferents in the SNc (Chen and Rice, 2002). These findings are consistent with the dominance of glutamate input to VTA DA neurons (70% of axodendritic synapses) and the dominance of GABA input to SNc DA cells (70% of axodendritic synapses)
(Bolam and Smith, 1990). Whether local glutamate input enhances or inhibits somatodendritic DA release (via GABA afferents) thus depends on the balance between excitatory and inhibitory inputs at a given moment (Chen and Rice, 2002), and, as such, can vary according to brain region, the pattern of local input circuitry, and experimental conditions.
In keeping with the expression of nicotinic ACh receptors by DA neurons (primarily a4B2-subunit-containing; Picciotto et al., 1998; Champtiaux et al., 2003), nicotine/ACh facilitatory control of somatodendritic DA release has been identified in VTA using microdialysis with a remote, subcutaneous nicotine administration (Rahman et al., 2003), and more directly in a dendrosomal preparation from SN/VTA using a [3H]DA release assay (Reuben et al., 2000). Although the effect of nicotinic ACh receptor activation on DA cells is typically excitatory, inhibitory effects can also occur by subsequent activation of Ca2+-activated K+ channels (Fiorillo and Williams, 2000). An additional facilitatory regulation of somatodendritic DA release may be offered by endogenous ATP acting at P2 receptors in VTA, according to experiments using microinjection of P2 receptor antagonists and microdialysis (Krugel et al., 2001). Specific P2Yrreceptor immunoreactivity on neurons in VTA suggests, but does not confirm, that these P2 receptors may be localized directly on DA neurons. Somatodendritic DA release may also be regulated by other classes of molecules, including reactive oxygen species; endogenously generated hydrogen peroxide (H202) can suppress DA release in the SNc, although not in the VTA (Chen et al., 2002).
Thus, in addition to the role of major synaptic inputs in the direct modulation of DA neuron output activity, these systems can powerfully and variously gate the release of somatodendritic DA. As a consequence, the action of somatodendritic DA release at D, and D2 receptors in VTA and SN will modulate the influence of synaptic input on the final signal integration and the ultimate activity of all dopaminoceptive output neurons of the VTA, SNc and SNr.
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